1. Neural circuit plasticity in a rat model of compulsive self-administration of drug This project is to investigate neural circuit plasticity along the course of addiction in a compulsive drug use model of rats. Compulsive drug seeking and taking are important characteristics of drug addiction. Our recent study showed that striatal-frontal circuits underlie the compulsive (or loss of control over drug use) symptoms in human cocaine users. Since human studies are often limited to cross-sectional investigations, we back-translated the findings from the human study to a rat model of compulsive self-administration of drug to examine addiction processes from the initial use of the drug to the stage of compulsive use and finally to the phase of abstinence. Causal relationships between drug intake, neural circuit plasticity and compulsive behaviors can be assessed in the longitudinal study. Rats underwent three phases: 1) self-administration (SA) of drug, 2) SA coupled with punishment (electrical shock), and 3) abstinence. Behavioral assessments and MRI scans were done at the baseline (before SA) and in the end of each phases. The aims of the study are to investigate 1) the plasticity of brain circuits across the SA, SA+shock, and abstinence phases; 2) the plasticity of brain circuits underlying the compulsive drug seeking and taking behaviors; and 3) the plasticity of brain circuits underlying cue-induced reactivity during abstinence. Data collection for the first phase of the study aiming to identify neural circuit plasticity has be completed. Data analysis is underway and a manuscript on the study is in preparation. (Manuscript in preparation) 2. Effects of nicotine exposure on the functional connectivity organization of the brain in adult rats This project seeks to understand the effects of nicotine exposure on brain organization in adult rats. Imaging and behavioral data have been collected at the baseline (before nicotine exposure), the end of 14-days of nicotine exposure, and the end of 14-days withdrawal. Analyses are underway to assess the brain-behavior relationships. The aims of the study are: 1) to examine whether functional connectivity of the striatal-cingulate circuits is associated with the withdrawal behaviors, as revealed in our previous studies of smoking in humans showing a negative correlation between striatum-dACC connectivity and FTND; 2) to investigate the dynamics of resting-state functional connectivity (frequency of states and transition between states) in rat brains and their relationship with the withdrawal behaviors; and 3) to assess whether individual differences in the brain organization as described by functional connectivity between brain networks can predict the withdrawal behaviors. (Manuscript in preparation) 3. Effects of nicotine exposure on adolescent rats This project seeks to describe and understand adolescent and adult nicotine withdrawal behavior. The first phase of the project is to examine dose-dependent changes in the somatic and affective signs of withdrawal in adolescents and adults exposed to nicotine. Adolescents began treatment at three different developmental stages, early, mid and late adolescence, to further understand the effects of age of nicotine exposure on withdrawal behaviors. Preliminary analyses indicate that adolescent and adult rats display different withdrawal behaviors in that the withdrawal signs are not present until the adult period, which may explain the difficulty in quitting smoking for long-term smokers, most of whom start in adolescents. A manuscript on the study of the first phase is in preparation. The second phase of the experiment is to examine changes in resting state functional connectivity, anatomical connections as well as levels of inhibitory and excitatory neurotransmitters in adolescents and adults exposed to nicotine, with the addition of neuroimaging to the previous experimental paradigm. Imaging and behavioral data of this phase have been collected, and analyses of these data are currently underway. (Manuscript in preparation) 4. Neurorestorative effects of 9-cis retinoic acid on stroke brain The purpose of this study was to examine the neurorestorative effect of delayed 9 cis retinoic acid (9cRA) treatment for stroke. Adult male rats received a 90-min right distal middle cerebral artery occlusion (dMCAo). Animals were separated into two groups with similar infarction sizes, based on magnetic resonance imaging on day 2 after dMCAo. 9cRA or vehicle was given via an intranasal route daily starting from day 3. Stroke rats receiving 9cRA post-treatment showed an increase in brain 9cRA levels and greater recovery in motor function. 9cRA enhanced the proliferation of bromodeoxyuridine (+) cells in the subventricular zone (SVZ) and lesioned cortex in the stroke brain. Using subventricular neurosphere and matrigel cultures, we demonstrated that proliferation and migration of SVZ neuroprogenitor cells were enhanced by 9cRA. Our data support a delayed and non-invasive drug therapy for stroke. Intranasal 9cRA can facilitate the functional recovery and endogenous repair in the ischemic brain. (Yu et al., Sci Rep. 2017)